1. Field of the Invention
The invention relates to a method of treating inflammatory, including ocular and/or dermal, diseases and conditions having inflammation as a component of such ocular and/or dermal diseases and conditions, with cyclosporine derivatives. In particular, the present invention relates to a method for the treatment of allergic conjunctivitis, aqueous deficient dry-eye state, phacoanaphylaxis endophthalmitis and uveitis using certain novel cyclosporine derivatives.
2. Description of the Related Art
Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation—swelling, redness, pain, heat, and loss of function—due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring.
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation since the lymphatic system doesn't have the capacity to compensate for it, and the increased blood flow to the area causes the reddened color and increased heat. The blood vessels also alter to permit the extravagation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.
Chronic inflammation is a pathological condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterized by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, prolonged exposure to chemical agents such as silica, tobacco smoke, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated.
The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved by the chemically-induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma. The increased collection of fluid into the tissue causes edema.
Acute inflammation is characterised by marked vascular changes, including vasodilation, increased permeability, and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood—a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischemic heart disease.
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise deregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:                Asthma        Autoimmune diseases        Chronic inflammation        Chronic prostatitis        Glomerulonephritis        Hypersensitivities        Inflammatory bowel diseases        Pelvic inflammatory disease        Reperfusion injury        Rheumatoid arthritis        Transplant rejection        Vasculitis.        
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary damage to tissues. Failure to do so results in chronic inflammation, cellular destruction, and attempts to heal the inflamed tissue. One intrinsic mechanism employed to terminate inflammation is the short half-life of inflammatory mediators in vivo. They have a limited time frame to affect their target before breaking down into non-functional components, therefore constant inflammatory stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include                TGF-β from macrophages        Anti-inflammatory lipoxins        Inhibition of pro-inflammatory molecules, such as leukotrienes.        
Specific diseases and conditions of the eye having an inflammatory component include allergic conjunctivitis, phacoanaphylactic endophthalmitis and uveitis. These diseases and conditions can be located throughout the eye, in both the posterior and anterior chambers of the eye as well as in the vitreous body.
Uveitis, the inflammation of the uvea, is responsible for about 10% of the visual impairment in the United States. Phacoanaphylactic endophthalmitis is a human autoimmune disease.
Panuveitis refers to inflammation of the entire uveal (vascular) layer of the eye. Posterior uveitis generally refers to chorioretinitis, and anterior uveitis refers to iridocyclitis. The inflammatory products (i.e. cells, fibrins, excess proteins) of these inflammations are commonly found in the fluid spaces if the eye, i.e. anterior chamber, posterior chamber and vitreous space as well as infiltrating the tissue intimately involved in the inflammatory response. Uveitis may occur following surgical or traumatic injury to the eye; as a component of an autoimmune disorder, i.e. rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, sarcoidosis; as an isolated immune mediated ocular disorder, i.e. pars planitis, iridocyclitis etc., unassociated with known etiologies; and following certain systemic diseases which cause antibody-antigen complexes to be deposited in the uveal tissues. Together these disorders represent the non-infectious uveitis.
Cyclosporins have been used to treat inflammatory conditions including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases. Specific auto-immune diseases for which Cyclosporin has been proposed or applied include, autoimmune hematological disorder (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia), systemic lupus erythematosus, poly-chondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease) endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type 1), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy). (See U.S. Pat. No. 6,346,511.)
Thus, it will be understood that it is desirable to develop compounds that are useful in treating inflammatory diseases and conditions. It has been found that the compounds disclosed herein may be used to treat various inflammatory diseases and conditions.
Such compounds include the methylthio-substituted cyclosporin A and other alkylthio-substituted cyclosporin A derivatives described in PCT application Nos. 98-379455, 98-379456 and 98-379457, which have been found to be active against certain retroviruses, especially AIDS (acquired immunodeficiency syndrome) and ARC (AIDS-related complex) when administered orally, parenterally, rectally or by inhalation. In addition, these compounds have generally been found to have only a very weak immunosuppressant action, and to show anti-retroviral activity at non-cytotoxic and non-cytostatic concentrations. These compounds are claimed to have a synergistic action with other agents active against retrovirus (such as inhibitors of reverse transcriptase, protease, integrase, HIV replication and nucleocapside). (See also U.S. Pat. Nos. 5,944,299; 5,977,067; 5,965,527 and 5,948,755).
These compounds are also claimed for use in the treatment of ocular diseases and conditions in U.S. Pat. Nos. 6,350,442 and 6,254,860.
Thus, it is one object of this invention to treat inflammatory diseases and conditions, including diseases and conditions having inflammation as a component thereof, with cyclosporine derivatives.
It is another object of this invention to provide cyclosporine A derivatives to treat ocular diseases and conditions, such as allergic conjunctivitis.
It is one object of this invention to treat ocular diseases and conditions, including ocular diseases and conditions having inflammation as a component thereof, with cyclosporine derivatives.
It is another object of the invention to treat dermal diseases and conditions, including dermal diseases and conditions having inflammation as a component thereof, with cyclosporine derivatives.
It is another object of the invention to treat dermal conditions, such as psoriasis and dermatitis.
Other objects of this invention will become apparent from a reading of the present specification.